2-(p-phenylbenzyl)oxazolines in treating inflammation

ABSTRACT

2-(P-PHENYLBENZYL) OXAZOLINES ARE DISCLOSED WHICH ARE PREPARED BY REACTING P-PHENYLPHENYLACETIC ACIDS WITH AMINO-ALCOHOLS UNDER DEHYDRATING CONDITIONS. THE COMPOUNDS POSSESS ANTI-INFLAMMATORY ACTIVITY.

United States Patent 3,777,031 Z-(P-PHENYLBENZYL) OXAZOLINES IN TREATING INFLAMMATION Ying-Ho Chen and Carl Dalton Lunsford, Richmond,

Va., assignors to A. H. Robins Company, Incorporated, Richmond, Va.

No Drawing. Application Sept. 9,1971, Ser. No. 179,237,

now Patent No. 3,726,893, which is a continuation-inpart of abandoned application Ser. No. 82,159, Oct. 19, 1970. Divided and this application Dec. 29, 1972, Ser. No. 319,545

Int. Cl. A61k 27/00 U.S. Cl. 424-272 13 Claims ABSTRACT OF THE DISCLOSURE 2-(p-phenylbenzyl)oxazolines are disclosed which are prepared by reacting p-phenylphenylacetic acids with amino-alcohols under dehydrating conditions. The compounds possess anti-infiammatory activity.

The present application is a division of our prior-filed copending application Ser. No. 179,237, filed Sept. 9, 1971, now US. Pat. 3,726,893, which was a continuation-in-part application of our prior-filed application Ser. No. 82,159, filed Oct. 19, 1970, noW abandoned.

The present invention relates to anti-inflammatory agents and is more particularly concerned with certain 2-(p-phenylbenzyl)oxazolines which possess a high degree of anti-inflammatory activity, the preparation thereof, therapeutic compositions containing said oxazolines as active ingredient and a method of use of said compounds and compositions to alleviate inflammation and symptoms thereof in a living animal body.

The anti-inflammatory agents of the present invention are preferably compounds having the formula:

wherein;

R and R are hydrogen, lower-alkyl and hydroxyloweralkyl,

R is hydrogen and lower-alkyl, and

R is hydrogen, fluorine, bromine, chlorine and trifluoromethyl.

Formula I In the structural formula ,given above, the asterisks(*) serve to point out the asymmetric carbon atoms present in many of the compounds of the present invention, for example, when R and R are dissimilar. When two asymmetric centers are present, pairs of diastereoisomers are possible. These diastereoisomers, together with their optically active forms, are included within the scope of the present invention.

The novel compounds of the present invention at 316 mg./kg. (per os) reduced the response to pleural irritation. The anti-inflammatory action of the novel compounds was demonstrated using a modification of the Evans Blue-Carrageenan Pleural Elfusion test [Sancilio,

Patented Dec. 4, 1973 were determined relative to phenylbutazone, the standard anti-inflammatory agent.

Activity of Oxazolines in the Six-Hour Evans Blue-canageenan Pleural Efiusion Assay Percent Example Dose 1 reduction Mg./kg. per as.

It is, accordingly, an object of the present invention to provide novel compounds which have a high degree of anti-inflammatory activity. An additional object is the provision of compounds having anti-inflammatory activity and which produce minimal side eifects.

Another object is to provide certain novel 2- (p-phenylbenzyl)oxazolines. A still further object is to provide therapeutic compositions containing the same and methods for the utilization thereof. Other objects of this invention will be apparent to one skilled in the art and still other objects will become apparent hereinafter.

In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout this specification the terms have the following significance.

The term loWer-alky as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, amyl, hexyl, octyl, and the like.

The p-phenylphenylacetic acids starting materials and the aminoalcohols'used in the present invention are either commercially available or they can be prepared by methods well known to the art.

METHOD OF PREPARATION The preparation of the 2-(p-phenylbenzyl)oxazolines (I) may be accomplished by mixing and reacting a pphenylphenylacetic acid (II) with an aminoalcohol (III). The reaction sequence is illustrated by the following:

a --rincoon HmoR R cmoH II R1 l LR:

3 wherein R R R and R have the values given hereinabove.

A general procedure for the preparation of the 2-(pphenylbenzyl)oxazolines (I) is as follows:

A stirred mixture of one part of a p-phenylphenylacetic acid (II), one and one-tenth parts of an aminoalcohol (III) and 500 parts of a water immiscible organic solvent such as benzene, toluene, xylene, tetralin, phenyl ether and the like is refluxed in a system containing a water trap for a period of from about four hours to about four days during which period the water formed during the reaction is separated in the trap. After the theoretical amount of water has separated, the hot reaction mixture is filtered and the oxazoline (I) is isolated from the filtrate by a suitable procedure. When at least one of the substituents in the 4-position of the oxazoline ring is hydroxymethyl, the product separates from the cooled filtrate as a well-defined crystalline material. When one or both substituents in the 4-position are lower-alkyl radicals, the product is usually a low melting solid which is isolated by concentration of the filtrate and distillation in vacuo f the residue to give the oxazoline which crystallizes on standing.

Optically active oxazolines are readily prepared as described hereinabove by using optically active aminoalcohols as starting materials. Examples 8 and 9 in Table HI were prepared using optically active aminoalcohols.

The oxazolines can also be prepared by cyclization of a-(p-phenylphenyl)-N-substituted acetamides in a dehydrating medium as described hereinabove. The acetamides which are usually well-defined crystalline solids are prepared by reacting p-phenylphenylacetyl halides with aminoalcohols in a suitable solvent.

The following examples are given by way of illustration and are not limiting.

EXAMPLE 1 2- (p-phenylbenzyl -4-hyd roxymethyl-4- methyloxazoline A solution of 32.0 g. (0.15 mole) of p-phenylphenylacetic acid and 17.5 g. (0.17 mole) of 2-amino-2-methyl- 1,3-propanediol in 600 ml. of xylene was refluxed overnight using a Dean-Stark trap during which time the theoretical amount of water separated. The reaction mixture was filtered while hot and the filtrate was cooled to room temperature. The white crystals which formed on standing were separated by filtration and washed with water on the filter until the filtrate was of neutral pH. Recrystallization of the solid from xylene gave 25 g. (59.5%) of product which melted at 116-118" C.

4 Analysis.Calcd. for C I-I NO (percent): C, 76.84; H, 6.81; N, 4.98. Found (percent): C, 77.14; H, 6.77; N, 4.91.

EXAMPLE 2 2- (p-phenylbenzyl) -4,4-bis-hydroxymethyloxazoline 2- (p-phenylbenzyl) -4,4-dimethyloxazoline Using the procedure of Example 1, p-phenylphenylacetic acid and 2-amino-2-methyl-l-propanol were reacted together in refluxing xylene to give 2-(p-phenylbenzyl)-4,4-dimethyloxazoline (M.P. 5456 C.) in 87.7% yield.

Analysis.Calcd. for C H NO (percent): C, 81.47; H, 7.22; N, 5.28. Found (percent): C, 81.31; H, 7.22; N, 5.31.

EXAMPLE 4 2- p- (4-fiuorophenyl) benzyl] -4-hydroxymethyl- 4-methyloxazoline Using the procedure of Example 1, p-(4-fluorophenyl) phenylacetic acid and 2-amino-2-methyl-1,3-propanediol were reacted together in refluxing xylene to give a 48.4% yield of 2-[p-(4-fluorophenyl)benzyl]-4-hydroxymethyl- 4-methyloxazoline which melted at -107 C.

Analysis.--Calcd. for C H No F (percent): C, 72.22; H, 6.06; N, 4.68. Found (percent): C, 72.07; H, 6.08; N, 4.74.

EXAMPLE 5 2- (p-phenylbenzyl) oxazoline Using the procedure of Example 1, p-phenylphenylacetic acid and Z-aminoethanol are reacted together in refluxing xylene to give 2-(p-phenylbenzyl)oxazoline.

EXAMPLES 6-18 Examples 6-18 were prepared using the procedure of Example 1. The physical data are summarized in Table III.

TABLE III Analysis (B P.) M.P., Caled. Found Example R ZR R R CJmm. C H N C H N OH; H E18 59-61 76. 30 6. 40 4. 94 76. 12 6. 43 4. 01 H H 53. 55 81. 24 6. 82 5. 57 81. 20 6. 83 5. 55 H H H 52-54. 5 81. 24 6. 81 5. 57 80. 86 6. 87 5. 42 H H H 81. 24 6. 82 5. 57 81. 06 6. 91 5. 08 (3 H; H H H 36-38 81. 47 7. 22 5. 28 80. 78 7. 25 5. 27 (CHOrCH H H H (160-2/ 01) 81. 17 7. 57 5. 26 81. 04 7. 57 5. 04 CH; 3 OH; H 55- 81. 39 7. 59 4. 61 81. 48 7. 22 5. 28 H OH; H (-5/.05) 81. 48 7. 22 5. 28 80. 38 7. 24 5. 12 CH3 CH2 H 67-6 72. 82 7. 39 4. 46 73. 53 7. 03 4. 47 OH; H M-Cl 113-115 68. 46 5. 74 4. 43 68. 17 5. 79 4. 55 H H p-F (124-6/0.1) 76. 30 6. 40 4. 94 75. 81 6. 21 4. 78 CH3 H m-F 4. 93 5. 05 OH; H m-Cl 4. 67 4. 53

1 d-isomer prepared using d-2-am1no-1-propanol. 1-lsomer prepared using 1-2-amino-1-propanol.

EXAMPLE 19 When, in the procedure of Example 1, there is substituted for p-phenylphenylacetic acid an equivalent amount of the following:

p-(3-trifluoromethylphenyl)phenylacetic acid, p-(3-bromophenyl)phenylacetic acid, and p-(4-bromophenyl) phenylacetic acid,

there are obtained 2- [p- 3 -trifluoromethylphenyl) benzyl] -4-hydroxymethyl-4-methyloxazoline,

2- [p- 3-bromophenyl) benzyl] -4-hy droxymethyl-4- methyloxazoline, and

2- [p- (4-bromophenyl) benzyl] -4-hydroxymethyl-4- methyloxazoline.

FORMULATION AND ADMINISTRATION The present invention also contemplates novel compositions containing the compounds of the invention as active ingredients. In forming the novel compositions of this invention, the active ingredient is incorporated in a suitable carrier, illustratively, a pharmaceutical carrier. Suitable pharmaceuitcal carriers which are useful in formulating the compositions of this invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, propylene glycol, glycerine, glucose syrup and the like.

Although small quantities of the active materials of the present invention are eifective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are fifty or one hundred milligrams. Fifty to 100 milligrams appear to be optimum per unit dose, while usual broader ranges appear to be 50 to 300 milligrams per unit dose.

The following are examples of compositions formed in accordance with this invention.

( 1) Capsules Capsules of 50 mg. and 100 mg. of active ingredient per capsule are prepared.

Typical blend for encapsulation: Per capsule, mg. Active ingredient 50.0 Lactose 251.7 Starch 129.0 Magnesium stearate 4.3

Total 435.0

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:

In each case, uniformly blend the selected active ingredient with lactose, starch, and magnesium stearate and encapsulate the blend.

(2) Tablets A typical formulation for a tablet containing 50.0 mg. of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium phosphate.

Per tablet, mg.

( 1) Active ingredient 50.0 (2) Milo starch 20.0 (3) Corn starch (paste) 38.0 (4) Lactose 90.0 (5) Calcium stearate 2.0 (6) Dicalcium phosphate 120.0

Total 320.0

mg. tablet-- Ingredients: Per tablet, mg. Active ingredient 100.0 Lactose 190.0 Dicalcium phosphate 172.2 Starch 54.0 Milo starch 21.6 Calcium stearate 2.2

Total 540.0

Uniformly blend the active ingredient, lactose, dicalcium phosphate, starch and milo starch. This blend is granulated with water and the wet mass is passed through a number eight mesh screen. The wet granules are dried at -460 degrees Fahrenheit overnight. The dried granules are passed through a number ten mesh screen. These dried granules are blended with the proper weight of calcium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, methods, and procedures of the present invention Without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims. A

What we claim is:

1. A method of alleviating inflammation in a living animal which comprises administering orally to said animal an effective amount of a compound having the formula:

wherein;

R and R are each selected from the group consisting of hydrogen, lower-alkyl and hydroxy lower-alkyl,

R is selected from the group consisting of hydrogen and lower-alkyl, and

R is selected from the group consisting of hydrogen,

fluorine, bromine, chlorine and trifluoromethyl.

2. A method as defined in claim 1, wherein the active anti-inflammatory agent is administered together with a pharmaceutically acceptable carrier and in amounts of about 50 to 300 milligrams.

3. The method of claim 2 wherein the active antiinflammatory agent is 2-(p-phenylbenzyl)-4-hydroxymethyl-4-methyloxazoline.

4. The method of claim 2 wherein the active antiinfiammatory agent is 2-(p-phenylbenzyl)-4methyloxazoline.

5. The method of claim 2 wherein the active agent is 2- p-phenylb enzyl) -4,4-dimethyloxazoline.

6. The method of claim 2 wherein the active agent is 2- p-phenyla-methyl) benzyl] -4,4-dimethyloxazoline.

7. The method of claim 2 wherein the active agent is 2- [p-phenylet-methyl benzyl] -4-methyloxazoline.

8. A therapeutic composition in the form of a tablet, capsule and a liquid suitable for the alleviation of inflammation comprising (1) an effective amount of about 50 to 300 milligrams of an anti-inflammatory active compound having the formula:

wherein;

R and R are each selected from the group consisting of lower-alkyl and hydroxy lower-alkyl,

R is selected from the group consisting of hydrogen and lower-alkyl,

R is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and trifiuoromethyl, and

(2) a pharmaceutically acceptable carrier therefor.

9. A composition as defined in claim 8 wherein the active anti-inflammatory agent is 2-(p-phenylbenzyl)-4- hydroxymethyl-4-methyloxazoline.

10. A composition as defined in claim 8 wherein the active anti-inflammatory agent is 2-(p-phenylbenzyl)-4 methyloxazoline.

11. A composition as defined in claim 8 wherein the active anti-inflammatory agent is 2-(p-phenylbenzyl)-4,4- dimethyloxazoline.

12. A composition as defined in claim 8 wherein the active anti-inflammatory agent is 2-[p-phenyl-(u-methyl) benzyl] -4,4-dimethyloxazoline.

13. A composition as defined in claim 8 wherein the active anti-inflammatory agent is 2-[p-phenyl-(u-methyl) benzyl]-4-methyloxazoline.

References Cited UNITED STATES PATENTS 3,235,557 2/1966 Wiggins et a1 260307 STANLEY J. FRIEDMAN, Primary Examiner 

